277
XOTES
1.00 g. of l~~-acetylthio-4,6-androstadiene-3,l7-dione, m.p. 229-229.5' (dec.), was obtained. Anal. Calcd. for CZ1H2603S:C, 70.36; H, 7.31. Found: C, 70.38; H, 7.33. Ultraviolet spectrum: Ah:no1 287 mM, t 23,400. [CY]D4-68'. 1CY, 7a-Dithiol-l1@,17~~,81-trih ydroxy-4-pregnene-S,BO-dione FRICK CHEMICAL LABORATORY 21-acetate 1,7-dipropionate. 11&17~t,21-Trihydroxy-1,4,6PRINCETON UNIVERSITY pregnatriene-3,aO-dione 21-acetate,E 0.87 g., dissolved in PRINCETON, N. J. 1.0 ml. of propanethiolic acid, was heated on the steam bath for several hours. Most of the excess thiolic acid was removed under vacuum and the residue was chromatographed on silica gel. The column was washed with benzene and Addition of Alkanethiolic Acids to mixtures of 5 and 10% ethyl acetate in benzene. Then the column was eluted with 15% ethyl acetate in benzene and A1-4~6-3-0xosteroids the eluants were concentrated to yield 0.20 g. of I C Y , ~ C Y dithiol-ll~,17~,2l-trihydroxy-4pregnene-3,20-dione 21-aceROBERTC. TWEIT A N D R. M. DODSON tate 1,7-dipropionate as a glass. Anal: Calcd. for C28H400sS~: C, 59.97; H, 6.94. Found: C, 59.91; H, 7.05. Ultraviolet spectrum ?A:' Received September 25, 1958 239 mu, E 21,200; [CY]D +37'. 1a,7cr-Dithiol-17p-hydrox~(-4-androstm-3-one triacetate. 178Recently some selective additions to A1s4,6-3- .4cetoxy-1,4,6-androstatrien-3-one,s 1.93 g., was mixed with oxosteroids have been reported. Nussbaum and co- 2.0 ml. of ethanethiolic acid and heated and irradiated with workers' have reported the epoxidation of the 6,7- an ultraviolet light for 45 min. Some of the excess thiolic double bond, and Kirk and Petrow2 recorded the acid was diRtilled under vacuum, ether was added to the addition of chlorine to the 1,Zdoublebond. We have residue, and the solid which formed was separated by filtration. Two crystallizations of this material from acetoneobserved mono- and di- a.dditions of alkanethiolic ether yielded 0.91 g. of 1~~,7~~-dithiol-l7~-hydroxp-4-androsacids to the A1~4~6-3-ketones. When 1,4,6-andro- ten-3-one triacetate, m.p. 199-200' (dec.). Anal. Caled. for C2SH840SS2: C, 62.73; H, 7.16. Found: C, statriene-3,17-dione was heated with ethanethiolic 237.5 mM, E acid, a monoadduct separated rapidly from the hot 62.68; H, 7.46. Ultraviolet spectrum: A::hano1 20,100; [ a ]-46'. ~ solution. The same product was obtained from a 1 ~~,7cu-Dithiol-l7~~,B1-dihydroxy-4-pregnene-S,11 ,2O-trione chloroform solution of equimolar amounts of triene 1,7,8l-triacetate. 17~~,2l-Dihydroxy-l,4,6-pregnatriene-3,11,and thiolic acid irradiated with an ultraviolet lamp. 20-trione 21-acetate,' 0.54 g., was dissolved in 1.0 ml. of On the basis of its ultraviolet spectrum ( X ~ ~ ~ h " n o ' ethanethiolic acid and heated and irradiated with an ultralight for 1 hr. Then part of the excess acid was re287 mp, e 23,400) and of analogy to the addition of violet moved under vacuum and ether was added. The solid which thiolic acids to A1~4-3-oxosteroids,this product was formed was separated by filtration and crystallized from assigned the structure, 1a-acetylthio-4,6-andro- acetone-ether to yield 0.38 g. of 1~~,7~~-dithiol-17~~,21-dim.D. hvdroxv-4-~reznene-3.11.20-trione 1.7.21-triacetate, ~tadiene-3~17-dione. , . In the cases of 17P-acetoxy-1,4,6-androstatrien-i90-i9io ( i e c j . Calcd. for C27H340sS2: C, 58.89; H, 6.22. Found: %one, 17a,2l-dihydroxy-1,4,6-pregnatriene-3,11,20- C,Anal. 59.05; 58.72; H, 6.70, 6.53. Ultraviolet spectrum: A?:' trione 21-acetate, and l l P , 17a,2l-trihydroxy-l14,6-235.5 mp, e 18,500; [CY]D$80'. Anal. Calcd. for CIJl,4Nz02. 2Cd&N&: C, 41.5; H, 3.2; N, 17.6. Found: C, 41.6; H, 3.0; N, 17.7. It should be pointed out that neither 11,111,nor IV can be satisfactorily extracted from aqueous solution with organic solvents.
I
pregnatriene-3,20-dione 21-acetate, the products isolated were di-adducts (exhibiting maxima in the 240 mp region characteristic of A4-3-ketones). Again by analogy to mono addition^,^ these compounds were assigned the 1a,7a-diacylthio structures. EXPERIMENTAL4
1~~-Acetylthio-4,6-androstadiene-S,I7-dione. 1,4,6-Androstatriene-3,17-dione,6 2.00 g., was dissolved in 5.0 ml. of ethanethiolic acid and irradiated and heated with an ultraviolet light for 1 hr. During this time crystals formed. They were separated by filtration, washed with ether, and crystallized from methylene chloride-methanol. In this way
(1) A. L. Kussbaum, G. Brabazon, T. L. Popper, and E. P. Oliveto, J . Am. Chem. SOC.80, 2722 (1958). (2) D. N. Kirk and V. Petrow, J . Chem. Soc., 1334 (1958). (3) R. M. Dodson and R. C. Tweit, J . Am. Chem. Soc., in press. (4) We wish to thank Dr. R. T. Dillon and his staff of the Analytical Division for the microanalyses and optical determinations reported. The rotations were taken in chloroform at 24 =k 1". The melting points were taken on a FisherJohns melting point apparatus. ( 5 ) S. Kaufman, J. Pataki, G. Rosenkranz, J. Romo and C. Djerassi, J . Am. Chem. SOC.,72, 4531 (1950).
,
DIVISIONOF CHEMICAL RESEARCH G. D. SEARLE & Co. CHICAGO 80, ILL. (6) D. Gould, E. L. Shapiro, H. L. Herzog, hI. J. Gentles, E. B. Hershberg, W. Charnep, M. Gilmore, S. Tolksdorf, M. Eider, P. 1,.Perlman, and M. M. Pechet, J . Am. Chem. Soc., 79,502 (1957).
Synthesis of 1,2,4,5-Tetrachloroben~ene-l-C1~~ RICHARD W. MEIKLE Received September &9, 1968
1,2,4,5-Tetrachlorobenxenehas been under investigation in this laboratory for use as an agricultural chemical. The compound, labeled with chlorine-36, was desired for residue determinations using an isotope dilution procedure. Since it had not previously been prepared the synthesis was undertaken employing the Sandmeyer reaction.
278
NOTES
EXPERIMENTAL
VOL.
24
There was no depression in a mixed m.p. with an authentic sample of 1,2,4,5-tetrachlorobeneene. The excess chloride-Cla6used in this synthesis was recovered from the reaction mixture by treatment with barium hydroxide solution to precipitate the sulfate and phosphate, conversion to hydrochloric acid-Cla6 by meana of DowexdO exchange resin in the acid form, and finally, titration of the eluate with dilute sodium hydroxide solution followed by evaporation to dryness.
Cuprous chEoride-C1aE.lTo a solution of cupric sulfate pentahydrate (187 mg., 0.75 mmole) and sodium chlorideCl36 (44 mg., 0.75 mmole, specific activity 20.8 pc./mmole) in 0.6 ml. of water was added dropwise with shaking at room temperature, sodium sulfite (96 mg., 0.76 mmole) in 0.3 ml. of water. The mixture was centrifuged, the aqueous phase was removed with a dropper, and the precipitate of cuprous chloride-C13* was washed once with 0.5 ml. of water AQRICULTURAL RESEARCH LABORATORY to which was added a very small amount of sulfurous acid Dow CHEMICAL Co. to prevent oxidation. This aqueous phase was also removed SEALBEACH,CALIF. by centrifugation. The cuprous chloride-CP was washed three times each with acetic acid, anhydrous ethanol, and anhydrous ether, centrifugation being used each time to separate the liquid Stereochemistry of 8,10-Dimethyl-2-ketophase. The product was used immediately in the next reaction. A1'g;3a4-hexahydronaphthalene The yield in preliminary runs was quantitative. I,f?,~,5-TelrachZorobenzene-l-Cla~. 2,4,5-Trichloroaniline STANLEY M. BLOOM (147 mg., 0.75 mmole) was diazotized in the following manner? The aniline derivative was dissolved in 0.75 ml. of concentrated sulfuric acid. To this ice cold solution was added Received October 6, 1958 1.88 ml. of a cold solution of sodium nitrite (1.125 mmole) in concentrated sulfuric acid. Cold 85% phosphoric acid In the reported synthesis of 8,lO-dimethyl(0.75 ml.) was then added and the dark colored solution was (Ia) the reallowed to stand at room temperature for 1.5 hr. Initially 2-ket0-A~.~;~,~-hexahydronaphthalene and rather slowly, there was some precipitation, but the lationship between the methyl groups was unascrystalline material gradually redissolved on intermittent signed.' The work described in this note establishes shaking as the reaction progressed. The reaction solution was finally poured onto ice to give a solution with a volume the missing stereochemical link and allows the of about 10 ml. The excess nitrous acid was destroyed by assignment of (Ib) for the cyclohexadienone. addition of small quantities of urea. During the 1.5 hr. required for the diazotization reaction to take place, the cuprous chloride4186 was prepared as 4 described above. Following this, a solution of the cuprous ch10ride-CI~~(0.75 mmole) and sodium chloride-Cla6 (65 -0 R mg., 1.13 mmole) in hydrochloric acid-CP (0.6 ml. of 1.64 N CHs acid, 0.98 mmole, specific activity 20.8 pc./mmole) was preIa ( R = u C H 3 ) IIa (R=....Hj pared. This solution contained B total of 2.86 mmole of Ib (R=*s.*CH3) I I b (R=-H) chloride-Cl36. Preliminary work had made it clear that a one-to-one stoichiometry, chloride to diazotized amine, gave a very poor yield of product. The cuprous chloride-Cls6 solution was heated on the c steam bath and the diazonium solution a t room temperature was rapidly poured onto it with shaking. After 15 min. of intermittent shaking at room temperature, the product was isolated by hot benzene extraction. The ben111 I\' zene solution was placed in a porcelain crucible (3.3 cm. i.d. a t the top) and the benzene was removed using the steam Reduction of the cyclohexadienone with lithium bath and a gentle stream of air. This evaporation was carried out carefully to prevent loss of product since tetra- in ammonia gave an oily saturated ketone which chlorobenzene sublimes very easily. is shown in the sequel to be identical with transThe product was purified by sublimation at atmospheric 2-keto-8 0-1 OB-dimethyldecalin (Ha) synthesized pressure in the following manner: The crucible containing the crude product was covered with a piece of Whatman No. from IV. The Diels-Alder adduct IV, in which the 1 filter paper (4.25 cm.) through which were punched a methyl groups are fixed in the desired manner, was large number of pin holes. This paper served to prevent made from the reaction of 4-methoxy-2,5-tolusublimed product from falling back into the crucible and, quinone with tran~-l,3-pentadiene.~,~ The adduct on more important, acted as a condensing surface for colored byproducts which do not sublime, but distill. The paper (1) S. M. Bloom, J . Am. Chem. SOC.,80, 6280 (1958). and crucible were covered with an inverted watch glass (4.2 (2) The trans-1,3-pentadiene employed in this study was cm.) which served as the condensing surface. The watch not separated from any cis contaminant (vide injra). Several glass was cooled with a gentle stream of air. The crucible prior investigations have shown that the cis-1,3-pentadiene was heated a t 275-285' for 1 hr. with the hot stage from a does not give a normal Diels-Alder adduct. For example, melting point apparatus. The tetrachlorobenzene condensed ci.s-1,3-pentadiene gives only polymeric material on reaction as long white needles, m.p. 137' (lit.* 137-141'). The yield with maleic anhydride. See D. Craig, J . Am. Chem. SOC., was 92 mg. (57%); the specific activity was 20.8 pc./mmole. 65, 1006 (1943); R. L. Frank, R. D. Emmick and R. S. Johnson, J . Am. Chem. SOC.,69, 2313 (1947); S. J. Averill (1) R. N. Keller and H. D. Wycoff, Inorg. Syntheses, Vol. and H. L. Trumbull, J. Am. Chem. SOC.,76, 1159 (1954) for a description of the dienophiles and the conditions employed. 11,l (1946). These facts led us t o conclude that the cis isomer would give (2) J. Schoutissen, J . Am. Chem. SOC.,55, 4531 (1933). (3) E. R. Huntress, Organic Chlorine Compounds, John only polymeric material on reaction with Pmethoxy-2,Bt oluquinone. Wiley & Sons, Inc., New York, 1948, p. 367.
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